In the End

The Building Blocks of Death

By Kathleen Yount

What doesn't kill you may make you stronger, but what kills you just makes you dead.

Under "cause," most of our death certificates will list some variation of heart disease. Others will list stroke or cancer. Some of us will have unfortunate accidents, and some of us will die of diseases such as Alzheimer's or the flu.

But we all know that we're eventually going to go, because there is one thing that guarantees that every one of us meets our maker: the aging process. It happens to us all in the end. And it starts at the ends—of our chromosomes, that is.

The molecular gatekeeper of aging is telo­merase, an enzyme that keeps the ends of our chromosomes—called telomeres—stable, so that our cells can divide and our tissues can regen­erate. Trygve Tollefsbol, Ph.D., D.O., who studies aging and directs UAB's Cell Senescence Culture Facility, uses the handy metaphor of a shoelace: Telomerase is that plastic cap at each end. Telomeres keep our genetic shoelaces from fraying, and telomerase is what keeps the telomeres intact.

Each time a cell replicates, its telomeres shorten. Telomerase stops that shortening process, and can do so indefinitely. But you and I aren't producing telomerase anymore—in fact, our telomerase production was shut down before we ever made it out of the womb. Almost all human cells stop manufacturing (more technically, "downregulate") telomerase very early on in fetal development. So, in a cellular sense, our countdown begins before we are born.

Though it is heart disease, respiratory failure, or some such malady that actually stills our hearts and minds, Tollefsbol explains that age is the grand weakness behind these ills. "What aging is, in essence," he says, "is a breakdown in the body's physiological ability to handle stress." This breakdown makes the older you more vulnerable than the younger you to life-threatening illnesses. A decreased vigor in the immune system can make it easier to succumb to influenza or pneumonia, for example; aging of the pancreas can lead to a less robust production of insulin and pave the way for diabetes.

Each species has its own genetically programmed countdown—mice last about two years, medium-sized dogs go for about 10, humans seem able to hang on for about 100, give or take a few decades. There are other factors, such as oxygen radicals, that can contribute to the aging process at the cellular and molecular level, but it's the ever-shortening chromosomal telomeres that are ultimately controlling the clock.

A Reason for Disease

Aging to death, in other words, is our genetic destiny. "Barring accident or an unusual infection, you'll be around for a good long while," says Tollefsbol, "but you're simply not going to live to be 1,000 years old, because your genes aren't programmed that way." It seems, he says, that the human body has decided that its optimal survival comes from promoting the genetic aging process and "letting the body check out after time."

Dont Eat To Live

Among their many research projects at the UAB Cell Senescence Culture Facility, Tollefsbol and his colleagues are studying caloric restriction and its effects on longevity. They have shown that sharply reducing food intake can significantly lengthen cell life—but while these studies can be enlightening at the cellular level, Tollefsbol sees the clinical use of extreme caloric restriction as a bit premature. “I think it’s impractical,” he says. “It can also be dangerous: the side effects of such restrictions aren’t fully understood, and limiting your nutrients could get you into trouble physiologically.” But mostly, Tollefsbol says, the problem is in the application. Simply put: “People just don’t like being hungry all the time.”

There's at least one good reason for this: cancer. Cancer cells love telomerase, because it allows them to keep on dividing indefinitely. In fact, some new approaches to cancer therapies are telomerase-based. They are designed to shut down the endless cellular reproduction made possible when mutations switch telomerase back on.

Yet even though telomerase is more likely to be activated in cancer cells, that's not what makes them cancerous, says Tollefsbol. "If you just gave a cell telomerase, it would allow that cell to live forever, but it wouldn't by itself cause cancer in that cell." In fact, he adds, there are very few types of mutations that by themselves cause cancer. Usually it's those unlucky cells that pick up three to six different types of mutations that become cancerous, and telomerase activation is just one of those mutations.

The aging process reduces the likelihood of cancerous growth, then, by limiting cellular proliferation in general. This all falls in line with one of the popular current theories of aging: that it evolved to prevent cancers. "Aging can be seen as a tumor suppressor mechanism," says Tollefsbol. That might sound contradictory, since the single most important risk factor for cancer is advancing age. But Tollefsbol says that at the cellular level, the aging process may prevent many more cancers than it permits.

"Life causes cancer," he says. As we age we get exposed to more environmental hazards and pick up more mutations. It could be that without our cellular aging process, cancers would run rampant in our bodies before we even reached our reproductive peaks.

Path to the Fountain of Youth?

"If you look at a photograph from the 1870s, you know that all the people in that photograph are gone," says Tollefsbol. "One may have gotten run over by a train, one may have died of TB, one may have been shot. But you know that they're all gone, and that's because aging is the final killer." It's a killer that many scientists are working to slow down, stop, even reverse. And in a petri dish and the occasional worm, they've been able to do so. "We can allow cells to live forever by adding telomerase, so the question is whether we can do that for a whole organism." But you can't just paint a telomerase glaze on a person and halt the aging process. "Humans have so many different types of cells in our bodies," he says, and they don't all behave—or age—in the same way.

Some researchers think that our ability to manip­ulate telomerase and other aging processes will soon increase so much that humans will be able to live to be 1,000 years old. Tollefsbol is not one of these believers, but he admits that science may be able to give their cause a boost. If through only a few minor genetic mutations, researchers already can allow a worm to live 50 percent longer than its normal life span, then perhaps, Tollefsbol says, we will ultimately be able to do that with humans, too.

But these goals must be pursued in an incremental fashion, and for now the main line of inquiry leads to our short-lived friends, the mice. "There are several million dollars in prizes for those who can extend the life span of a mouse to unprecedented lengths," says Tollefsbol. While he himself isn't going out for that money, he does think it's possible—as is the dream of extending canine life spans to 25, and human ones to 200. "I think it's doable, and I think it will happen, but it's going to happen at the genetic level," he says. "We are all programmed to age, and we'll have to tinker with our genes to change that."

What about the current implications of this work? "What most of us want to live is a full, healthy life-and then to go fast," Tollefsbol says. "We don't want to linger for 15 years with an awful disease. So the goal of our research is to use our improving understanding of the molecular aging process to extend the lives of people as much as possible and to have them be fairly healthy up to their deaths."